期刊
HUMAN GENETICS
卷 137, 期 6-7, 页码 553-567出版社
SPRINGER
DOI: 10.1007/s00439-018-1910-3
关键词
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资金
- National Natural Science Foundation of China [81501852, 81472046, 81772299, 81472045, 81772301]
- Beijing Natural Science Foundation [7172175]
- Beijing Nova Program [Z161100004916123]
- Beijing Nova Program Interdisciplinary Collaborative Project [xxjc201717]
- 2016 Milstein Medical Asian American Partnership Foundation Fellowship Award in Translational Medicine
- Central Level Public Interest Program for Scientific Research Institute [2016ZX310177]
- PUMC Youth Fund [3332016006]
- Fundamental Research Funds for the Central Universities [3332016006]
- CAMS Initiative Fund for Medical Sciences [2016-I2M-3-003, 2016-I2M-2-006, 2017-I2M-2-001]
- Distinguished Youth Foundation of Peking Union Medical College Hospital [JQ201506]
- 2016 PUMCH Science Fund for Junior Faculty [PUMCH-2016-1.1]
- US National Institutes of Health, National Institute of Neurological Disorders and Stroke [NINDS R01NS058529, R35NS105078]
- National Human Genome Research Institute/National Heart, Lung, and Blood Institute [NHGRI/NHLBI UM1 HG006542]
- National Human Genome Research Institute [NHGRI K08 HG008986]
- NATIONAL HUMAN GENOME RESEARCH INSTITUTE [K08HG008986, UM1HG006542] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS058529, R35NS105078] Funding Source: NIH RePORTER
With the recent advance in genome-wide association studies (GWAS), disease-associated single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) have been extensively reported. Accordingly, the issue of incorrect identification of recombination events that can induce the distortion of multi-allelic or hemizygous variants has received more attention. However, the potential distorted calculation bias or significance of a detected association in a GWAS due to the coexistence of CNVs and SNPs in the same genomic region may remain under-recognized. Here we performed the association study within a congenital scoliosis (CS) cohort whose genetic etiology was recently elucidated as a compound inheritance model, including mostly one rare variant deletion CNV null allele and one common variant non-coding hypomorphic haplotype of the TBX6 gene. We demonstrated that the existence of a deletion in TBX6 led to an overestimation of the contribution of the SNPs on the hypomorphic allele. Furthermore, we generalized a model to explain the calculation bias, or distorted significance calculation for an association study, that can be 'induced' by CNVs at a locus. Meanwhile, overlapping between the disease-associated SNPs from published GWAS and common CNVs (overlap 10%) and pathogenic/likely pathogenic CNVs (overlap 99.69%) was significantly higher than the random distribution (p < 1 x 10(-6) and p = 0.034, respectively), indicating that such co-existence of CNV and SNV alleles might generally influence data interpretation and potential outcomes of a GWAS. We also verified and assessed the influence of colocalizing CNVs to the detection sensitivity of disease-associated SNP variant alleles in another adolescent idiopathic scoliosis (AIS) genome-wide association study. We proposed that detecting co-existent CNVs when evaluating the association signals between SNPs and disease traits could improve genetic model analyses and better integrate GWAS with robust Mendelian principles.
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